Pompeo was born in Everett, Massachusetts, the daughter of Kathleen B. (née O'Keefe) and Joseph E. Pompeo, a salesman. Her father was of Italian, English, and Irish descent, while her mother was of Irish ancestry. She was raised Roman Catholic. Her mother died of a painkiller overdose when Ellen was four, and her father remarried soon after. Her father died on September 1, 2012. She has five siblings: three sisters and two brothers. She was nicknamed the pencil, and Stracciatella (an icecream flavor).
Pompeo landed her first major role in 2005, on the ABC medical drama Grey's Anatomy, which is now in its tenth season, as the title character, Meredith Grey, a surgical intern attending at a prestigious hospital. In 2011, she was named the ninth highest paid television actress, earning $7 million. In 2011, she signed a new contract for Grey's Anatomy that increased her salary to US$200,000 per episode. On May 10, 2012, it was announced that she signed a contract for two more seasons. In 2012, she was named the eighth highest paid television actress, earning $9 million. She has extended her contract for two more years which would have her involved with the show until the 12th season.
On October 13, 2007, Pompeo was honored by the National Italian American Foundation for her achievement in entertainment at a black-tie gala in Washington, D.C. On October 27, 2011, Deadline.com reported that Pompeo had launched her own production company called Calamity Jane which sold its first project to ABC, an untitled show about female agents on the Secretary of State's security detail
Pompeo suffers from the chronic respiratory disease asthma, but the time in her life when she was initially diagnosed and the severity of her case were not known as of late April of 2014.